Dual Nickel Photocatalysis for O-Aryl Carbamate Synthesis from Carbon Dioxide

We report the use of dual nickel photocatalysis in the synthesis of O-aryl carbamates from aryl iodides or bromides, amines, and carbon dioxide. The reaction proceeded in visible light, at ambient carbon dioxide pressure, and without stoichiometric activating reagents. Mechanistic analysis is consistent with a Ni(I–III) cycle, where the active species is generated by the photocatalyst. The rate-limiting steps were the photocatalyst-mediated reduction of Ni(II) to Ni(I) and subsequent oxidative addition of the aryl halide. The physical properties of the photocatalyst were critical for promoting formation of O-aryl carbamates over various byproducts. Nine new phthalonitrile photocatalysts were synthesized, which exhibited properties that were vital to achieve high selectivity and activity.


■ INTRODUCTION
O-Aryl carbamates are found in pharmaceuticals and natural products (Scheme 1A). 1 Traditionally, they are synthesized starting from amines, alcohols, and toxic phosgene or its derivatives (Scheme 1B). 2 In such synthesis, phosgene sequentially reacted with the amine and the alcohol in either order. While the reaction worked well for the synthesis of a variety of carbamates, electron-poor or heteroaromatic phenols tended to react in poor yields. 2b,3 Additionally, a reaction route without toxic reagents is desired. Carbon dioxide is a potential replacement for phosgene in carbamate formation. It is a nontoxic, renewable, and easily available C1 reagent, but its use is limited by its thermodynamic stability. 4 Its use has already been well demonstrated in carbamate synthesis with aliphatic alcohols, where an oxygen-abstracting reagent was often used to drive the reaction. 4c,5 However, O-aryl carbamates are exceedingly difficult to obtain from phenols due to the instability of the phenol−acyl bond.
An alternative approach is to directly couple the carbamate anion, formed from an amine reacting with carbon dioxide, with an aromatic group (Scheme 1C). Previously, this strategy was used with aryl iodium, aryl sulfonium, oxidative coupling of boronic esters, and C−H activation with directing group activated copper catalysis. 6 These methods required large excesses of amine, high temperatures and pressures, or stoichiometric reagents. The employed high temperatures were especially problematic, as this disfavors carbamate formation, which must be compensated for with elevated pressures of CO 2 .
Recently, dual nickel photocatalysis has attracted attention in heteroatom−carbon coupling reactions of aryl (pseudo)-halides with various nucleophiles, such as amines, 9 alcohols, 10 carboxylic acids, 11 amides, 12 and thiols. 13 Photocatalysis has been typically conducted at moderate temperatures, which we reasoned would enable CO 2 -based synthesis of O-aryl carbamates at ambient pressure, while simultaneously providing sufficient driving force to couple the carbamate anion with aryl halides (Scheme 1D). 14 ■

RESULTS AND DISCUSSION
We used previous studies on dual nickel-photocatalyzed aryl halide heteroatom couplings as a starting point, 15 and after initial optimization we managed to get up to a 78% yield, with 4-iodobenzotrifluoride, morpholine, and CO 2 ( Table 1, entry 1). The reactions required the nickel complex, photocatalyst, and visible light to proceed (entries 2−4). Compact fluorescent lamps (CFL) gave the product in higher selectivity than blue LEDs (entry 5). The 4,4′-di-tert-butyl-2,2′-bipyridine (dtbbpy) ligand was important for this reaction as was reported also in the previous studies (entry 6). Amine and TMG loading could be further reduced with a minor decrease in yield (entries 7 and 8). The used conditions significantly influenced the yield of carbamate 3 by changing the selectivity of competing side reactions (Table 1, entries 9−17). These were N-arylation 4, phenol formation 5, and protodehalogenation 6. N-arylated products 4 are formed from direct amine coupling, 16 which was likely caused by residual amounts of free amine from the amine−carbamate equilibrium. Stronger bases such as Cs 2 CO 3 , 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), or tetramethylguanidine (TMG) pushed this equilibrium toward the carbamate formation, thus giving higher selectivity compared to weaker amine bases (Table 1, entries 9−12, Supporting Information (SI) Table S5). TMG and DBU may also have an additional role as a reducing agent, even though their reduction potentials are usually slightly higher than secondary amines (DBU 1.26 V, TMG 1.24 V (SI Figure S23) vs secondary amines 0.9−1.1 V). 17 Phenol 5 was mainly formed by side reactions with either residual water or oxygen as they both increase phenol formation from ca. 3% to ca. 10% (Table 1, entries 13−14, SI Table S13). 18 Oxygen is a known triplet quencher, but it did not have a large impact in this reaction, nor did added stilbene (entries 14−15). Organic photocatalyst, tetradiphenylaminophthalonitrile (7a, 4DPAPN), provided better results than classical Ir(ppy) 3 ( Table 1, entry 16). This was mainly due to the lower amount of protodehalogenation product 6. Another organic photocatalyst, a more reductive tetracarbazolisophthalonitrile (4CzIPN), also gave more dehalogenation product (entry 17). Protodehalogenation likely proceeds through photoreduction of aryl halide to form an aryl radical followed by hydrogen atom transfer. 19 It took place in the absence of nickel and was affected by the reductive properties of the photocatalyst. To further increase the selectivity, we synthesized and characterized a series of tetradiarylaminephthalonitriles 15a,20 with different electron-donating substituents to improve the photocatalytical properties (Table 2). We observed that a large E(PC/PC − ) correlates with an increased activity, while a smaller E*(PC*/PC − ) roughly correlates with increased selectivity. However, for photocatalysts with a very low E*, the reaction stops almost completely as was seen with MeOsubstituted 7b, 8b, and 9b. This was likely because the photocatalysts were not able to oxidize the amine or TMG at this point. From the studied photocatalysts, 4DPAPN-t Bu 7c had the highest selectivity with high activity and therefore was chosen for further studies.  With the optimized conditions, we studied the substrate scope of the reaction (Scheme 2). A variety of secondary alkyl amines, both cyclic and acyclic, were used in the reaction with 4-iodobenzotrifluoride 1 providing the product carbamate in good to moderate yields. Typically, 1 was completely consumed overnight, and protodehalogenation selectivity limited the yield. 4-Bromobenzotrifluoride was also studied, which generally gave slightly poorer yields than with 4iodobenzotrifluoride, but for carbamates 14, 15, and 18, only traces were observed. In these cases, also the conversion was very low, indicating that the amine or carbamate anion inhibits the catalyst. Compounds 14, 15, and 18 contain an additional carbonyl group which may have caused competitive coordination to the metal. Increased amine/carbamate coordination to the metal could inhibit oxidative addition, which was more significant for the less reactive bromo compounds. Using more intense blue LEDs gave a higher yield than with white light CFLs. With amines that have high conversion, using blue LEDs provided a slightly lower yield due to increased dehalogenation. The analogous triflate yielded no carbamate 3, only the corresponding phenol. Primary amines yielded no carbamate product; instead, the corresponding N-arylated amine was the major product. Primary aryl amines also yielded N-arylated product, but secondary aryl amines were unreactive (SI, Figure S7).
Various electron-deficient aryl iodides were compatible, and the yield was increased by the more electron-withdrawing substituents (Scheme 3). High selectivity was observed for iodo reactivity over bromo (25−27), and only traces of bromo coupled product were observed for bromoiodobenzenes. However, some dehalogenation of the product was still observed. More electron-rich aryl iodides required a longer reaction time and very electron-rich substituents are unreactive (28,29).
Iodopyridines could also be used as substrates (Scheme 3, 30−33). Corresponding products are known to be be difficult to prepare from the phenol starting material due to tautomerization. 3 Moderate yields were obtained for substituted 2-, 3-, or 4-iodopyridines. It was observed that the desired carbamates 30−33 could react further with excess amine to form unwanted ureas, reducing the overall yield. The use of only 1.1 equiv of the amine suppressed the urea formation. Of the studied pyridines, the highest yield was obtained for 2-methoxy-3-iodopyridine 33, which was likely because of the electron-donating methoxy-substituent stabilized carbamate 33 against urea formation.
We further investigated why primary amines yielded Narylated amine instead of the carbamate. We first studied if O-  The Journal of Organic Chemistry pubs.acs.org/joc Article aryl carbamates derived from primary amines decomposed under the reaction conditions. Independently synthesized Nbutyl-carbamate 34 was placed under the reaction conditions, but even after 3 days there was no observable decomposition (Scheme 4A). We then repeated the reaction in the absence of carbon dioxide. This led to the formation of N-arylated product in 13% yield which indicates that this was not the cause for poor reactivity. We also studied if carbamate−amine equilibrium was causing the direct amine reactivity (Scheme 4B; see SI Table S16 for details). With stronger base Cs 2 CO 3 or BuLi, the reactivity was nearly fully suppressed, which may have been caused by a lack of suitable reducing agent in the absence of TMG or secondary amine. To study this, we added 0.2 equiv of trimethylamine as a reductant, which provided full conversion and yielded 31% N-arylated product 39. However, no carbamate 38 was formed. Increasing TMG from 2 to 5 equiv also did not afford carbamate 38. Instead, even higher selectivity toward N-arylation was observed. This effect could be explained by the carbamate anion 36 reacting directly from the nitrogen instead of having to dissociate to the amine 37. Direct N-arylation of carbamate under standard reaction conditions was supported by cyclic carbamate 40 reacting in 50% yield (Scheme 4C). 12 O-Arylation of primary carbamates was therefore heavily disfavored in the reaction conditions as not even traces of the product were detected, while N-arylation was even more favored since it could take place even without decarboxylation. Previous studies on other nickel catalyzed carbon− heteroatom coupling reaction have suggested a small number of alternative mechanisms. 11a,21 A major difference was how the reductive elimination proceeds. One of two mechanisms was usually suggested in C−N and C−O coupling reactions: Energy transfer from photocatalyst to Ni(II) complex; or alternatively, a Ni(I−III) cycle that is propagated by the photoredox cycle. Overall, both of these have been shown to be plausible mechanisms and can likely take place concurrently. The major pathway is dependent on the minute details of the reaction. Compared to the most related esterification reaction using the 4DPAPN photocatalyst, which was thought to proceed through the energy transfer mechanism, 15a they observed significant quenching of reactivity when the reaction was conducted in the presence of air. In Table 1, entry 14, it was shown that addition of pure oxygen has only a very modest effect on the yield, which suggests that our reaction proceeds through a different mechanism.
To gain insight into the mechanism of this reaction, we measured the reaction profile as a function of time with 19 F-NMR (Figure 1; see SI part 13 for details). There was a ca. 6 h induction period when using 0.1% of the photocatalyst 4DPAPN-t Bu 7c, and the reaction did not reach the maximum rate. When the loading of photocatalyst was increased to 0.5%, the induction period was reduced to 2 h. A loading of 1.0% minimized the induction to a mere 30 min. These observations suggest that the photocatalyst facilitated the reduction of nickel to the active form. With only 1 equiv of tetramethylguanidine and morpholine the reaction rate was roughly the same as with 2 equiv, but the conversion only reaches around 80% conversion. When 5% nickel was used, the maximum reaction rate was reached with 0.5% of 4DPAPN-t Bu 7c, and the reaction reaches completion after 7 h. However, less dehalogenation was observed with 0.1% of 4DPAPN-t Bu 7c, which resulted in higher yield. When irradiation was stopped after the activation period, the reaction stopped very quickly   Figure 1) and there was no detected conversion in the dark. After the irradiation was continued, the reaction proceeded without a new activation period, indicating that the catalyst resting state was different from the initial inactivated form. While this behavior was indicative of the energy transfer mechanism, similar results were also observed in C−N coupling, which proceeded through the Ni(I−III) cycle. 21 This observation could be explained by fast deactivation by comproportionation, which requires constant reactivation by the photocatalyst. The potential intermediate dtbbpyNi(II)(o-tolyl)Br 42 was synthesized to determine whether reductive elimination was mediated by the excited state or by Ni(III). It was catalytically active and yielded 78% of carbamate 3 with photocatalyst, 12% without, and 0% in the dark (Scheme 5A); however, no o-tolyl carbamate 44 was detected.
When compound 42 was mixed with 3 equiv of tetramethyl guanidium morpholine carboxylate and irradiated with or without photocatalyst, only toluene was observed. With the addition of an oxidant, ferrocenium tetrafluoroborate, formation of o-tolyl morpholine-N-carboxylate was observed (Scheme 5B). This suggested that the reductive elimination proceeded through a Ni(III) species instead of an excited Ni(II)*. With only 1 equiv of tetramethyl guanidium morpholine carboxylate, no product was generated. Instead, some bromotoluene was observed, suggesting incomplete replacement by the carbamate ion. This would also explain why a moderate excess of the carbamate anion was beneficial for the reaction.
To further study if light had an additional effect beyond reducing the nickel, we used zinc as a reductant in the dark (Scheme 5C). With 1 equiv of zinc, full conversion was obtained, but only 10% carbamate 3 formed. When this reaction was repeated in light, but without photocatalyst, 32% carbamate was obtained (see SI, Table S17 for further details). Alternatively, when already reduced Ni(COD) 2 was used as the nickel source instead to synthesize carbamate 3, the reaction gave <1% yield in dark, 10% yield in light, and, with 4DPAPN-t Bu7c, a 27% carbamate yield (Scheme 5D). However, even in the presence of the photocatalyst, the Ni(COD) 2 -derived catalyst deactivates long before reaching full conversion (SI, Figures S52−54). Overall, these findings suggest that while the carbamate was formed only through the nickel(III) complex instead of direct photoexcitation, light could still facilitate the reaction in some way. Irradiation of similar nickel(II) complexes to 42 was reported to promote formation of Ni(I) and Ni(III) species via photoinduced disproportionation, which could explain the effect of light when Zn or Ni(COD) 2 was used. 22 This could also be a minor pathway in the reaction, but since the yield was quite low, it is unlikely to be the main mechanism.
Reaction profiles were measured for different concentrations of the reagents 4-iodobenzotrifluoride 1, tetramethylguanadinium morpholine-N-carbaxylate, 4DPAPN-t BU 7c, and Ni-(dtbbpy)Br 2 (Scheme 6A; see SI, chapter 13 for details), and approximate rate orders were determined from the maximum rate of the sigmoidal reaction curve. The substrate 4iodobenzotrifluoride had first rate order, while the tetramethylguanadinium morpholine-N-carbaxylate was zeroth order. The nickel complex had 0.3 rate order, and the photocatalyst had a 0.5−0.6 rate order. Fractional rate order constants for the nickel and the photocatalyst suggest that they affect the concentration of the active nickel catalyst in a complex way. This could be explained by the active nickel I or III becoming deactivated Ni(II) via comproportionation or in a reaction with single electron transfer species generated by the photocatalyst (Scheme 6B). The nickel is then reactivated by the photocatalyst in a slow step. Table 1, entry 11 and Scheme 4B suggest that either TMG or the secondary amine can act as the terminal reductant. The side product formation had roughly the same rate orders as carbamate formation, taking in account error due to low concentration. An exception was dehalogenation reaction, which was zeroth order in terms of nickel concentration, suggesting it to be a solely photocatalyzed reaction.  Based on the mechanistic studies, the reaction behaved similarly to the amine-aryl halide coupling studied more thoroughly by MacMillan et al., 21 which proceeds through the Ni(I−III) cycle initiated and kept active by the photocatalyst (Scheme 6C). Compared to the reactions where energy transfer is the main mechanism, in this reaction we could not observe product with photoexcitation of the direct intermediate (Scheme 5B) and triplet quenchers had nearly no effect on the reaction (Table 1, entries 14, 15). 15a Overall, photocatalytic reduction of the initial Ni(II) to Ni(I) was followed by an oxidative addition of aryl halide to yield the Ni(III) complex. The coordinated halide was then replaced by the carbamate ion, as an excess of carbamate ion was vital for product formation in stoichiometric experiments (Scheme 5B). Reductive elimination yielded the product carbamate and regenerated the Ni(I) complex.

■ CONCLUSIONS
We have developed a method to synthesize O-aryl carbamates under mild conditions using visible light dual nickel photocatalysis, which avoids toxic phosgene, stoichiometric reagents, or high pressures of CO 2 . Several new photocatalysts were synthesized and characterized, which had a critical role in improving the selectivity of the reaction. Mechanistically, the reaction proceeded through the Ni(I−III) cycle, which was sustained by the photocatalyst. Our results support the mechanistic understanding of dual nickel photocatalyzed heteroatom−carbon coupling reactions.

■ ASSOCIATED CONTENT Data Availability Statement
The data underlying this study are available in the published article and its Supporting Information.